- Full (HTML) - Full (PDF) - Related EHP Articles - PubMed:Related Articles - PubMed:Citation - Cited in PMC - Purchase This Issue

Matthew R. Milnes,^1,* Adriana Garcia,¹ Emily Grossman,¹ Felix Grün,¹ Jason Shiotsugu,¹ Michelle M. Tabb,^1,** Yukio Kawashima,² Yoshinao Katsu,³ Hajime Watanabe,³ Taisen Iguchi,³ and Bruce Blumberg¹

¹Department of Developmental and Cell Biology, University of California, Irvine, California, USA; ²Japan NUS Co. Ltd., Tokyo, Japan; ³Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, Okazaki, Japan

Abstract
Background: Nuclear receptor subfamily 1, group I, member 2 (NR1I2) , commonly known as steroid and xenobiotic receptor (SXR) in humans, is a key ligand-dependent transcription factor responsible for the regulation of xenobiotic, steroid, and bile acid metabolism. The ligand-binding domain is principally responsible for species-specific activation of NR1I2 in response to xenobiotic exposure.

Objectives: Our objective in this study was to create a common framework for screening NR1I2 orthologs from a variety of model species against environmentally relevant xenobiotics and to evaluate the results in light of using these species as predictors of xenobiotic disposition and for assessment of environmental health risk.

Methods: Sixteen chimeric fusion plasmid vectors expressing the Gal4 DNA-binding domain and species-specific NR1I2 ligand-binding domain were screened for activation against a spectrum of 27 xenobiotic compounds using a standardized cotransfection receptor activation assay.

Results: NR1I2 orthologs were activated by various ligands in a dose-dependent manner. Closely related species show broadly similar patterns of activation ; however, considerable variation to individual compounds exists, even among species varying in only a few amino acid residues.

Conclusions: Interspecies variation in NR1I2 activation by various ligands can be screened through the use of in vitro NR1I2 activation assays and should be taken into account when choosing appropriate animal models for assessing environmental health risk.

Key words: endocrine disruption, metabolism, pesticides, phthalates, PXR, SXR, xenobiotics. Environ Health Perspect 116:880–885 (2008) . doi:10.1289/ehp.10853 available via http://dx.doi.org/ [Online 12 March 2008]

Address correspondence to B. Blumberg, Department of Developmental and Cell Biology, University of California, 5205 McGaugh Hall, Irvine, CA 92697-2300 USA. Telephone: (949) 824-8573. Fax: (949) 824-4709. E-mail: blumberg@uci.edu

*Current address: Conservation and Research for Endangered Species, Zoological Society of San Diego, Escondido, California, USA.

**Current address: Focus Diagnostics, Cypress, California, USA.

We thank J. Ycaza for assistance with plasmid preparations.

This study was supported by grants from the U.S. Environmental Protection Agency (STAR-CR830686) and an unrestricted research gift from Eisai Co, Ltd. to B.B. ; Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan ; a Health Sciences Research Grant from the Ministry of Health, Labour and Welfare, Japan, and a grant from the Ministry of Environment, Japan, to T.I. M.R.M. was supported by an institutional training grant from the National Institutes of Health (CA09054-29) and a University of California President's Postdoctoral Fellowship.

B.B. is a named inventor on U.S. patents related to SXR (6,756,491, 6,809,178, and 6,984,773) . The Salk Institute for Biological Studies (La Jolla, CA) , which has licensed them to various for-profit entities, controls these patents. The remaining authors declare they have no competing financial interests.

Received 5 September 2007 ; accepted 11 March 2008.